Epstein-Barr virus (EBV) infects over 95% of the population worldwide, and is associated with several human malignancies, such as Hodgkin's disease, Burkitt's lymphoma, nasopharyngeal carcinoma (NPC), and EBV-positive diffuse large B-cell lymphoma. EBV is a herpesvirus that latently infects human B cells in most individuals by adulthood. Persistent EBV infection is generally subclinical in immunocompetent hosts (Cohen, N. Engl. J. Med. 343:481-492 (2000)). However, immunocompromised patients are at high risk of developing EBV-induced B cell lymphoproliferative disorders (EBV-LPD) with significant morbidity and mortality (Shapiro et al., Blood 71:1234-1243 (1988)). Current treatment options for EBV-LPD include restoring the cellular immune responses to EBV and depleting the B cells with monoclonal antibodies or chemotherapy (Heslop et al., Blood 115:925-935 (2010); Khanna et al., Nat. Clin. Pract. Oncol. 2:138-149 (2005); Wagner-Johnston and Ambinder, Curr. Hematol. Malig. Rep. 2:249-254 (2007)). Restoration of cellular immune responses by adoptive transfer of ex vivo-generated EBV-specific cytotoxic T lymphocytes (CTL) has yielded promising results for treatment of EBV-LPD (Kanakry and Ambinder, Curr. Treat. Options Oncol. 14:224-236 (2013); Khanna et al., Proc. Natl. Acad. Sci. USA 96:10391-10396 (1999); Leen et al., Annu Rev. Immunol. 25:243-265; Long et al., Current opinion in immunology 23:258-264 (2011); Rooney et al., Lancet 345:9-13 (1995)). However, its application for the treatment of EBV-LPD is limited by the difficulties in generating enough numbers of EBV-specific CTL in vitro and the lack of in vivo expansion of infused CTL in patients with bulky disease (Leen et al., 2007; Louis et al., Blood 113:2442-2450 (2009)). Antibody-mediated targeting of EBV-infected B cells has unwanted side-effects as anti-CD20 antibody also depletes normal B cells, causing prolonged hypogammaglobulinemia; and finally, chemotherapy leads to unwanted off-target toxicity and also causes general immunosuppression (Leen et al., 2007).
γδ-T cells are considered as innate-like T lymphocytes with NK cell characteristics (Born et al., Curr. Opin. Immunol. 18:31-38 (2006); Carding and Egan, Nat. Rev. Immunol. 2:336-345 (2002)). Various innate signals, either alone or in combination with ligand recognition via the TCR, induce γδ-T cells to display innate-like immune functions (Bonneville and Scotet, Curr. Opin. Immunol. 18:539-546 (2006); Born et al., 2006; Zheng et al., Cellular & molecular immunology 10:50-57 (2013a)). γδ-T cells make up 1-10% of T lymphocytes in the blood and peripheral organs in adult humans. Most γδ-T cells in the peripheral blood and lymphoid organs of healthy human adults are Vγ9Vδ2-T cells. Vγ9Vδ2-T cells can be specifically activated in an HLA-unrestricted manner by small non-peptidic phosphoantigens, which are metabolites of isoprenoid biosynthesis pathways (Beetz et al., Immunobiology 213:173-182 (2008)). Isopentenyl pyrophosphate (IPP), an intermediate produced through the mevalonate pathway, was found to selectively activate and expand human Vγ9Vδ2-T cells in vitro and in vivo (Alexander et al., Clin. Cancer Res. 14:4232-4240 (2008); Puan et al., Int. Immunol. 19:657-673 (2007)). Pharmacological compounds, such as the aminobisphosphonate pamidronate, commonly used for the treatment of osteoporosis, can induce intracellular accumulation of IPP, leading to activation and expansion of human Vγ9Vδ2-T cells (Bonneville and Scotet, 2006). Human Vγ9Vδ2-T cells can exert broad antiviral and antitumor activities in vitro and in humanized mice in vivo (Fournie et al., Cellular & molecular immunology 10:35-41 (2013); Qin et al., J. virology 85:10109-10116 (2011); Qin et al., J. Infect. Dis. 205:1646-1653 (2012); Tu et al., J. experimental medicine 208, 1511-1522 (2011)). However, whether these cells have similar effects on EBV and EBV-LPD remains unknown.